Most of materials that are implanted in the organism or simply transiting inside thereof need to be at least biocompatible. Implantable materials often need to further have antirejection, cell antiproliferation and antibacterial properties.
For example, in order to avoid restenosis after stent implantation in an artery, the stent may have antirejection and/or antiproliferation properties. Chemists have developed a coating that may be physisorbed on the stent, said coating comprising an antirejection drug that is sustainingly released in blood.
Another example pertains to the field of ocular implants for which cell antiproliferation properties may be needed. Indeed, in order to avoid cataract, the sole efficient treatment consists in a surgical operation during which the crystalline lens is replaced by an intraocular implant (IOL). The most frequent post-operative complication of this treatment is the development of a cicatricial tissue around the implant, leading to an opacification and that is called secondary cataract. A second surgical operation is thus needed to solve this opacification problem. This side effect appears in 38% of patients about 9 years after the implantation of the IOL. Solutions are therefore expected to avoid secondary cataract and are searched through three main axes:                improvement of surgical methods: more precise methods are tested, especially in order to reduce the size of the incision and therefore avoid ocular traumatisms;        study of the implant geometry: it has been shown that certain forms of lens provide a mechanical barrier that avoid cell migration between the implant and the eye capsule;        use of new materials and/or surface treatments in order to improve biocompatibility and/or to bring new functionalities.        
Intraocular lens are mainly obtained from 3 types of materials: silicones, hydrophobic methacrylates and hydrophilic methacrylates. These materials are biocompatible and have convenient physical and optical properties. However, these materials do not have particular cell antiproliferation properties. Therefore, the development of new material or surface treatment bringing cell antiproliferation properties to IOL is needed. Further antibacterial properties are also of interest.
More generally, it is a general concern that implantable materials shall have cell antiproliferation properties in order to avoid colonization when implanted and further antibacterial properties are valuable to avoid the development of infections.
It was described in the prior art that certain chemical functions, when present at the surface of materials, may give cell antiproliferation and/or antibacterial properties to said material. Especially, mimicking heparin by using the association of carboxylate and sulfonate functions, in specific ratios, may confer cell antiproliferation and/or antibacterial properties to the substrate on which it is present.
Coatings comprising carboxylate and sulfonate functions of substrates for use in medical applications are for example described in U.S. Pat. No. 6,248,811. These coating are films which are first synthesized and isolated, then coated on the surface and finally grafted under UV radiative induction on the surface. Depending on the molar ratio of carboxylate functions to sulfonate functions, the coating polymers of U.S. Pat. No. 6,248,811 have:                antibacterial properties, for a molar ratio of carboxylate functions to sulfonate functions ranging preferably from 0.1 to 5;        antibacterial properties together with cell proliferation-inhibiting properties, for a molar ratio carboxylate/sulfonate ranging preferably from 0.4 to 2; or        cell proliferation-promoting properties, for a molar ratio carboxylate/sulfonate ranging preferably from 3 to 5.        
In this document, it is described that, depending on the value of the molar ratio of carboxylate functions to sulfonate functions, the coating polymers may have antibacterial properties and can be formulated so as to inhibit or promote cell proliferation. However, U.S. Pat. No. 6,248,811 discloses a method comprising several steps, i.e. the separate synthesis of the polymer, the isolation of the polymer, the coating of the polymer onto the substrate and then the graft of the polymer onto the coating by UV radiative induction. This technique is hardly industrially operable.
It is reported in the literature that a molar ratio of carboxylate functions to sulfonate functions equal to 1 could be optimum to inhibit cell proliferation, while displaying antibacterial properties. However, providing a thin grafted film (less than 100 nm), with a balanced 1:1 proportion of carboxylate functions and sulfonate functions is not made possible by the prior art techniques. Also, controlling the grafting of the material, and the presence of the ratio, may be a technical or quality-control issue, especially with thin coatings.
The present invention intends providing an implantable material presenting at its surface carboxylate and sulfonate functions in a 1:1 molar ratio, this ratio being securely and easily assessable and controlled.
Moreover, it is important that the coating comprising the carboxylate and sulfonate functions be chemically grafted on the implantable material, and not simply adsorbed thereon, in order to ensure a greater functional longevity to the material. Therefore, one object of the invention is to provide an implantable material chemically grafted on its surface with carboxylate and sulfonate functions in a 1:1 molar ratio.
In a preferred embodiment, implantable materials are organic implantable material, especially IOLs.
The process of manufacturing of the material chemically grafted carboxylate and sulfonate functions in a 1:1 molar ratio should be simple, reproducible and industrializable.
Known materials grafted with coatings comprising carboxylate and sulfonate functions are mainly obtained by first synthesizing and isolating a polymer comprising the carboxylate and sulfonate functions, the coating the polymer on the material and finally grafting it by chemical reaction, such as for example by UV curing as in U.S. Pat. No. 6,248,811.
U.S. Pat. No. 6,218,492 discloses a water-insoluble polymer, with antibacterial and/or antiproliferative properties. This polymer is synthesized by free-radical copolymerization of component I (containing a carboxyl group), component II (containing a sulfonic acid group), and component III (which is an aliphatically unsaturated monomer). The polymer may either be used as implantable constitutive material or being coated at the surface of an implant. However, this polymer presents low mechanical properties that render it difficult to be processed as constitutive material and affect its resistance overtime when coated as a layer.
Yammine et al. also described coatings comprising carboxylate and sulfonate functions (Yammine et al., Biomacromolecules, 2005, 6(5), 2630-2637). Especially, they developed photo-crosslinkable polymers bearing cinnamic, sulfonate and carboxylate functions to coat silicon intraocular lenses in order to reduce “secondary cataract” by inhibiting cell proliferation. The polymer is first synthesized by radical polymerization and then grafted on the IOL after coating by cycloaddition reaction of photosensible groups.
Methods presented above present the inconvenient to be at least two-steps methods, requiring first the synthesis of the polymer and then its grafting on the surface of the material. With these methods, the molar ratio of carboxylate function to sulfonate function cannot be precisely controlled in a simple and reproducible manner to obtain exactly a 1:1 molar ratio.
Coury et al. described, in in patent U.S. Pat. No. 5,278,200, heparin-like material and surfaces made by co-polymerization of acrylic acid (AA) and 2-acrylamido-2-methyl propane sulfonic acid (AMPS) in order to decrease bacterial and platelet adherence. The polymer may be first synthesized and then grafted on the material. The polymer may also be directly synthesized and grafted on the material by the generation of free radicals on the material surface (such as polyurethane surface), using Ce(IV) ions and radical copolymerization of AA and AMPS. However, grafting using Ce(IV) ions at the surface of the material presents, among others, the following drawbacks:                the method is not versatile as it may only be performed on materials comprising oxidizable functions at their surfaces;        cerium ions remain at the surface of the grafted material, which is incompatible with biological applications as cerium ions are toxic;        the polymerization should be performed under controlled atmosphere, need an energy intake as it has to be performed at 40° C. and is slow, usually at least 3 hours, in other words this method is not easily industrializable.        
Moreover, the control of the carboxylate to sulfonate functions cannot be precisely controlled in a simple and reproducible manner to obtain exactly a 1:1 molar ratio.
The Applicant previously developed a simple and efficient process to chemically graft carboxylate and sulfonate functions on implantable materials, especially on organic implantable materials such as IOLs. The method is described in patent application EP 12 172 281.3.
The process developed by the Applicant is based on a method which makes it possible to perform the grafting of organic polymer or copolymer films on the implantable material in the absence of an electric voltage (EP 2 121 814). This method, used under the name Graftfast®, makes it possible to graft films onto surfaces of various types, even non-conductive surfaces.
The Graftfast® method enables chemically grafting an organic film at the surface of a solid support. The method is based on chemical reactions, essentially radical reactions of chemisorption and polymerization, hereafter referred to as “copolymerization-like reaction”.
In classical radical polymerization or copolymerization, a first monomer is added on a radical initiator to form a radical building block, which constitutes the basis on which the polymer will grow. Further non-radical monomers, identical or different, are then successively added on the growing free radical copolymer as represented on FIG. 1-A.
Contrary to classical radical polymerization, in the copolymerization-like reaction of Graftfast®, the growing polymer does not bear a radical. It requires at each step the use of an activator to generate a radical entity which is then added on the growing polymer (FIG. 1-B).
The Graftfast® method may be implemented using adhesion primers as sole building entities. Adhesions primers are molecules capable of being chemisorbed at the surface of the substrate by radical reaction and comprising a further reactive function capable radical polymerization with another radical after chemisorption. Generally, the adhesion primer includes diazonium salts which strong reactivity ensures a robust covalent link between the polymer film and the substrate. The reaction of the diazonium salts with a chemical activator having reducing properties allows the reduction of the diazonium and generation of radicals. The activator may be a chemical agent but it may also be a physical condition, such as for example a given temperature or a photoactivation.
The adhesion primer, activated under the form of a radical, first reacts with the surface, forming a primary layer of adhesion. Simultaneously, further adhesion primers activated under the form of radicals react with this grafted primary layer of adhesion, to synthesize the film by radical polymerization directly on the surface.
The Graftfast® method may also be implemented using adhesion primers in combination with polymerizable monomers. The first steps of chemisorption of the adhesion primer on the surface and of its polymerization on the surface are the same as described above. At the same time, adhesion primers activated under the form of radicals react with the polymerizable monomers to form radical building blocks. This initiates the polymerization of the polymerizable monomer. Growing polymeric chains then react with the growing film anchored on the surface. A copolymer is thus directly synthesized on the surface by radical copolymerization after radical chemisorption of the adhesion primer.
Therefore, the Graftfast® method is implemented on a substrate using an adhesion primer, in a solvent, in presence of an activator and optionally in presence of polymerizable monomers. The film is simultaneously grafted and synthesized directly at the surface of the substrate.
The Graftfast® method had never been used to graft carboxylate and sulfonate functions in controlled ratio on implantable materials.
The Applicant performed an extensive research work to make it possible to carry out the Graftfast® technology for the specific goal of providing carboxylate and sulfonate grafted surfaces in a reproducible and controlled manner. It resulted in an implantable material grafted at the surface thereof with a film comprising carboxylate and sulfonate functions wherein the film is directly synthesized and grafted on said external surface by radical reaction of a source of carboxylate functions and a source of sulfonate functions, said sources being either polymerizable or chemisorbable and polymerizable.
Especially, this method was implemented using a chemisorbable and polymerizable adhesion primer having a carboxylate function in combination with a polymerizable monomer comprising a sulfonate function, leading to a film grafted on the surface.
In order to simply and reproductively obtain a molar ratio of carboxylate to sulfonate functions equal to 1, the Applicant sought to use bifunctional reactants, comprising one carboxylate function and one sulfonate function. By having the two functions on the same building block, the control of the ratio is automatically obtained.
However, the Applicant did not find any commercial compounds being susceptible to be used as adhesion primers in the Graftfast® technology. Therefore, the Applicant developed new functional adhesion primers having both one carboxylate function and one sulfonate function of Formula (I).
Moreover, the Applicant also developed bifunctional polymerizable monomers having both one carboxylate function and one sulfonate function of Formula (II), to be used together with any suitable adhesion primer in the Graftfast® technology.
Therefore, the invention relates to implantable materials grafted with a film simultaneously synthesized and grafted by contacting the surface of the material with a solution comprising the new bifunctional adhesion primer of Formula (I) or the bifunctional polymerizable monomer of Formula (II) of the invention, in conditions providing radicals.